Tertiary amino derivatives of dihydro-anthracene



Patented July 9, 1946 UNITED STATES PATENT OFFICE" TERTIARY AMINODERIVATIVES OF DIHYDRO-ANTHRACENE John w. Cusic, Slmkie, 111., assignorto G. n. Searle & 00., Skokie, 111., a corporation of Illi- 'nois NoDrawing. Application October 7, 1943, Serial No. 505,355

5 Claims.

CH2 CH2 /v and CH CH I; GH2-CH2 OHHMNRR CH- NR I QHr-CH:

wherein it stands for the integer 2 or 3 and R and R each represents anunsubstituted alkyl group containing not more thanfour carbon atoms. Itwill be noted that these compounds are structurally quite similar; thoseof Formula II can be derived from Formula I (where n is 3 and R is anethyl group) by a simple attachment of the R group to the first carbonin the side chain. These compounds have been tested and found to bepowerful and useful antispasmodic agents. Only the compounds representedby Formula I above are claimed in this application; the compoundsrepresented by Formula II are claimed in 9 applicant's copendingdivisional application Serial No. 593,541, filed May 12, 1945.

The prior art has disclosed several different categories of syntheticantispasmodic agents,

most of which, however, have been characterized by the presence of somefunctional group (as, for instance, an ester group) in addition to thetertiary amine group in the molecule. Blicke (J ournal of AmericanChemical Society, volume 61,

pages 91 and 771) has disclosed a series of terthose disclosed as activeby Blicke in that they have the one aralkyl group characterized by thedihydroanthracene nucleus, or that the nitro: gen is itself a part of acycloaliphatic ring.

I have found that the compositions of the present invention may beconveniently prepared by v the interaction of an alkali metalderivativev of dihydroanthracene with an appropriate dialkylaminoalkylhalide or N-methyl-4-halogen-piperie dine. The following is a detailedexample oi such preparation:

Example A solution of butyl lithium in dry ether is prepared in theusual manner from 2.7.4 gramsof n-butyl bromide and 2.8 grams oflithium. This solution is added gradually to a solution or suspension of18.0 grams of dihydroanthracene in dry ether, and the resulting;solution refluxed for about two hours. The whole'operation is preferablyconducted under an atmosphere of nitrogen.

' At the end'of this time, 15 grams of Y-diethylaminopropyl chloride areadded, and the resultant mixture stirred for twelve hours or morewithout heating. A small amount of alcohol is added to decompose anyunreacted organo-metallic compounds, and the reaction mixture isextracted with dilute hydrochloric acid. The acid extract is madealkaline, and the free base recovered by ether extraction of thisalkaline liquor and subsequent evaporation of the ether. It is an oilwhich can readily be purified by vacuum distillation; it boils at173-175 centigrade at 6 millimetres of pressure.

The free base readily forms salts with acids, most of which are solid,crystalline compounds which are more convenient to handle for use asmedicinals. Further, the salts are in general readily soluble in water,whereas the free base is quite insoluble in water. These salts may beobtained by neutralizing a solution of the base in dry ether with anabsolute alcoholic solution of the desired acid. Thus, the hydrochloridewas obtained as a crystalline compound which melts at 181-183centigrade.

The above example is merely illustrative; use of other aminoalkylhalides or of i-halogen-N- alkylpiperidines in the same procedure willyield the corresponding amines and salts thereof. Among other compounds,I have thus prepared the p-diethylaminoethyl, the p-dibutylaminoethyl,

the fl-diethylaminopropyl and the N-methylpiperidyl-4-derivatives of9,10-dihydroanthracene, together with their hydrochlorides and.

other salts.

In determining the utility of these substances as antispasmodic agents,I have found that -03- diethylaminoethyl)-9,10-dihydroanthracenehydrochloride is a preferred compound. Il1ustrative of its utility as anantispasmodic agent is the fact that, when tested on isolated strips ofrabbit intestine or uterus, it has shown a powerfu1 relaxing effect,both on untreated muscle and on muscle which had previously. beenstimulated by a drug such as acetylcholine or histamine. Quantitatively,its potency equals or surpasses that of such drugs as thediethylaminoethyl esters of fluorene-Q-carboxylic acid or ofdiphenylacetic acid, both of which are finding acceptance among themedical professions in this country, and approaches that of atropine.

The '1! diethylaminopropyl derivative was shown to be approximately aspotent as the above-cited compound in similar tests. Others will varyamong themselves somewhat, but all constitute a group of powerfulantispasmodic drugs. They also vary somewhat among themselves intoxicity, but in each case the toxic dose is greatly in excess of thetherapeutically effective dose, so that these compounds may be safelyadministered to man or animals in eflfective doses without untoward sideeffects.

It i to be understood that the amino compounds referred to in theappended claims are intended to refer to the bases described therein,whether they be in the form of thefreebase or of a salt with a non-toxicacid.

I claim:

1. New compositions of matter comprising tertiary amines of the formula:

wherein n stands for an integer between 1 and 4, and R and R eachrepresent unsubstituted alkyl 4 groups containing not more than fourcarbon atoms.

2. New compositions of matter comprising tertiary amines of the formula:

3. A new composition of matter comprising 9- (B-diethylaminoethyl)-9,10-dihydroanthracene of the formula:

CH2 C a CHzOHzNUhHsh 4. New compositions of matter comprising tertiaryamines of the formula:

(EHzCHaCHzNRR wherein R and R each represents an unsubstituted alkylgroup containing not more than four carbon atoms.

5. A new composition of matter comprising 9- (y-diethylaminopropyl)-9,10 dihydroanthracene of the formula::

C CHzCHaCHaIHCaHz)! JOHN' W. CUSIC.

